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Evaluation of a Potential Clinical Significant Drug-Drug Interaction between Digoxin and Bupropion in Cynomolgus Monkeys

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Abstract

Purpose

A three-period digoxin-bupropion drug-drug interaction study was performed in cynomolgus monkeys to assess the effect of bupropion and its metabolites on digoxin disposition.

Methods

Monkeys were administered either an i.v. infusion (0.1 mg/kg) or an oral dose of digoxin (0.2 mg/kg) as control. In single-dosing period, monkeys received an i.v. infusion of bupropion at 1.5 mg/kg together with an infusion or oral dosing of digoxin, respectively. During multiple-dosing period, bupropion was orally administered q.d. at 7.72 mg/kg for 12-day. Then it was co-administered with an i.v. infusion or oral dosing of digoxin, respectively. Renal expression of OATP4C1 and P-gp was examined.

Results

Bupropion significantly increased i.v. digoxin CLrenal0-48h by 1 fold in single-dosing period. But it had no effect on the systemic disposition of digoxin. In multiple-dosing period, bupropion significantly increased oral digoxin CLrenal0-48h, CLtotal0-48h, CLnon-renal0-48h and decreased its plasma exposure. Bupropion and its metabolites did not alter creatinine clearance. OATP4C1 was located at the basolateral membrane of proximal tubule cells, while P-gp was on the apical membrane.

Conclusions

The effect of multiple dosing with bupropion on the pharmacokinetics of digoxin is more pronounced. The magnitude of increase in digoxin CLrenal0-48h contributed to the decrease in AUC of digoxin in some extent, but certainly is not the major driving force. The lack of systemic exposure after a single dose but a significant decrease in exposure mediated by an increase in the digoxin CLnon-renal0-48h with repeated dosing is likely to be the more clinically relevant.

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Abbreviations

AQP1:

Aquaporin 1

AUC0-∞ :

Area under the plasma concentration-time curve from 0 to infinity

AUC0-48h :

Area under the curve from 0 to 48 h

BUP:

Bupropion

CLrenal0-48h :

Renal clearance from 0 to 48 h

CLtotal0-48h :

Total clearance from 0 to 48 h

CLnon-renal0-48h :

Non-renal clearance from 0 to 48 h

CLtotal :

Total clearance

CLfiltration :

Filtration clearance

CLrenal :

Renal clearance

CLnon-renal :

Non-renal clearance

CLcr :

Creatinine clearance

Cmax :

Maximal plasma concentration

DIG:

Digoxin

DDI:

Drug-drug interaction

EBUP:

Erythro-hydrobupropion

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

HF:

Heart failure

HBUP:

Hydroxybupropion

LC:

Liquid chromatography

MS/MS:

Tandem mass spectrometry

OATP:

Organic anion-transporting polypeptide

P-gp:

P-glycoprotein

SSRIs:

Selective serotonin reuptake inhibitors

TCAs:

Tricyclic antidepressants

TBUP:

Threo-hydrobupropion

Tmax :

Time of maximal plasma concentration

t1/2 :

Terminal half-life

Vss :

Volume of distribution at steady-state

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Acknowledgments and Disclosures

This work was supported by the National Nature Science Foundation of China (81530013 81603188 81370288), the China Postdoctoral Science Foundation (2017 M612165), Jiangxi Postdoctoral Science Foundation (2017KY24), the Natural Science Foundation of Jiangxi Province (20181BAB215045, 20151BAB215041), the Hospital Foundation of the second affiliated hospital of Nanchang University (2014YNQN2001), the Foundation of Educational Commission of Jiangxi Province (GJJ170156). We thank Prof. Jashvant Unadkat from University of Washington for critical review of the manuscript. None to declare.

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Author notes

  1. Yang Shen and Yang Yu contributed equally to this work.

Authors and Affiliations

  1. Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi,, China

    Yang Shen, Jiejing Jin, Xia Yan & Kui Hong

  2. The Department of Medical Genetics, The Second Affiliated Hospital of Nanchang University, Nanchang, China

    Yang Shen & Kui Hong

  3. Department of Pharmacy, The Second Affiliated Hospital of Nanchang University, Minde Road No.1, Nanchang, 330006, Jiangxi,, China

    Yang Yu, Aizhen Xiong & Jiake He

  4. Clinical Pharmacology Institute, Department of Pharmacy, Nanchang University, Bayi Avenue No. 461, Nanchang, 330006, Jiangxi,, China

    Yang Yu & Chunhua Xia

  5. Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, Minde Road No.1, Nanchang, 330006, Jiangxi, China

    Wei Lai, Shuai Li, Zixuan Xu, Jiake He & Kui Hong

  6. Clinical Pharmacokinetics Laboratory, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China

    Han Xing & Xijing Chen

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  1. Yang Shen
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Correspondence to Chunhua Xia or Jiake He.

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Shen, Y., Yu, Y., Lai, W. et al. Evaluation of a Potential Clinical Significant Drug-Drug Interaction between Digoxin and Bupropion in Cynomolgus Monkeys. Pharm Res 36, 1 (2019). https://doi.org/10.1007/s11095-018-2525-z

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  • DOI: https://doi.org/10.1007/s11095-018-2525-z

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